RNF4 is required for DNA double-strand break repair in vivo
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RNF4 is required for DNA double-strand break repair in vivo. / Vyas, R; Kumar, R; Clermont, F; Helfricht, A; Kalev, P; Sotiropoulou, P; Hendriks, I A; Radaelli, E; Hochepied, T; Blanpain, C; Sablina, A; van Attikum, H; Olsen, J V; Jochemsen, A G; Vertegaal, A C O; Marine, J-C.
In: Cell Death and Differentiation, Vol. 20, No. 3, 03.2013, p. 490-502.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - RNF4 is required for DNA double-strand break repair in vivo
AU - Vyas, R
AU - Kumar, R
AU - Clermont, F
AU - Helfricht, A
AU - Kalev, P
AU - Sotiropoulou, P
AU - Hendriks, I A
AU - Radaelli, E
AU - Hochepied, T
AU - Blanpain, C
AU - Sablina, A
AU - van Attikum, H
AU - Olsen, J V
AU - Jochemsen, A G
AU - Vertegaal, A C O
AU - Marine, J-C
PY - 2013/3
Y1 - 2013/3
N2 - Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiation-induced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.
AB - Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiation-induced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.
KW - Alleles
KW - Animals
KW - BRCA1 Protein
KW - Cell Line
KW - DNA Breaks, Double-Stranded
KW - DNA Repair
KW - Genotype
KW - Intracellular Signaling Peptides and Proteins
KW - Mice
KW - Mice, Transgenic
KW - Nuclear Proteins
KW - Rad51 Recombinase
KW - Radiation, Ionizing
KW - Sumoylation
KW - Transcription Factors
KW - Ubiquitination
U2 - 10.1038/cdd.2012.145
DO - 10.1038/cdd.2012.145
M3 - Journal article
C2 - 23197296
VL - 20
SP - 490
EP - 502
JO - Cell Differentiation and Development
JF - Cell Differentiation and Development
SN - 1350-9047
IS - 3
ER -
ID: 118896958